Although stents have revolutionized the treatment of atherosclerotic vessels by preventing vessel wall contraction, restenosis or re-narrowing of vessels, remains problematic, affecting more than 20% of more than one million annual stent procedures, increasing health care costs and limiting stent use to larger vessels. Restenosis begins following endothelial injury to blood vessels and is characterized by smooth muscle cell proliferation and matrix alterations. Studies show that restoring the endothelium reduces restenosis by blocking the exposure of smooth muscle cells to agents in the bloodstream. The thrombin peptide, TP508, which accelerates soft and hard tissue repair, is a potent angiogenic agent that stimulates proliferation and migration of endothelial cells. Because this peptide can safely stimulate tissue repair and revascularization with a single application, we hypothesize that TP508 may accelerate re-endothelialization, thereby reducing restenosis. Preliminary in vitro and in vivo data support this hypothesis. In the present studies, we will test the effects of long- and short-term exposure of TP508 to denuded carotid arteries, develop appropriate dosage protocols based on peptide bioavailability, and evaluate TP508 efficacy in an atherosclerotic rabbit model. These studies will determine the feasibility of phase II development of Th508 products to inhibit restenosis in man. PROPOSED COMMERCIAL APPLICATION: The use of coronary stents has grown significantly, with the worldwide stent market projected to reach $2.3 billion in 1999, with over 1,000,000 patients being treated annually. However, more than 20% of stented patients still have adverse closure of the vessel through restenosis. The ability to re-endothelizing the damaged vessel to reduce restenosis and tltrombosis with a TP508 stent coating could potentially benefit several hundred thousand patients per year, significantly reducing health care costs related to repeat procedures.